2-guanidinoalkyl-3,4-dihydro-2h-1,5-benzodioxepines



United States Patent 3,306,913 2-GUANEDENGALKYLGA-i)iHYDRO-2H-1,5-EENZGDHSXEENES .ioachirn Angst-sin and Aiastair Monro, Canterbury,Geoffrey W. H. Potter, Ramsgate, and Thomas I. Wrigley, Canterbury,England, assignors to Chas. Pfizer & Co., inc, New York, N.Y., acorporation of Delaware No Drawing. Filed Feb. 12, 19b5, Ser. No.432,396 Ciairns priority, application Great hritain, Feb. 14, 1964,6,225/64 Claims. (Ci. 26il34il.3

This invention relates to new and useful compounds in the field ofmedicinal chemistry. More particularly, it is concerned with certainnovel organic heterocycles which have been found to be useful astheraputic agents in view of the interesting biological properties theypossess.

The compounds which are included within the purview of the presentinvention are all selected from the class of organic bases of thefollowing general structural formula:

and the mineral and organic acid addition salts thereof, wherein each ofA and B is a member selected from the group consisting of hydrogen,chlorine, bromine, lower alkyl and lower alkoxy; n is an integer of fromone to four carbon atoms, and each of R R R R and R is a member selectedfrom the group consisting of hydrogen and lower alkyl. Typical membercompounds of this series include such Z-guanidinoalkyl-3,4-dihydro- 2lI-1,5-benzodio; ;epines as 2-guanidinomethyl-3,4-dihydro 2H1,5-benzodioxepine; 2-guanidinomethyl-7,8- dichloro-3,4-dihydro 2H 1,5b-enzodioxepine; 2-(3- guandinopropyl)-3,4-dihydro 2H1,5-benzodioxepine; 2(l-rnethylguanidino)methyl-3,4-dihydro 2H1,5-benzodioxepine; Z-guanidinomethyl 3 methyl-3,4-dihydro-2H-1,5-benzodioxepine, and the like. These compounds are all of value inthe treatment of hypertension.

The process employed for preparing the novel compounds of this inventioninvolves treating an appropriately substituted 2 aminoalkyl-3,4-dihydro2H 1,5-benzodioxepine compound with a guanidinoforming reagent of thefollowing type in the manner hereinafter described, viz; (l) by reactinga Z-aminoalkyl 3,4 dihydro-ZH- 1,5-benzodioxepine salt, such as thehydrochloride, with a cyanamide compound like cyanamide itself or withan appropriately substituted derivative thereof in the case of a2-aminoalkyl-3,4-dihydro 2H 1,5-benzodioxepine salt, or by fusionreaction of said amine salt with a dicyanamide compound to form thecorresponding 2- guanidinoalkyl-3,4-dihydro-2H-1,5 benzodioxepine saltdirect; (2) by reacting the Z-aminoalkyl-3,4dihydro-2H-LS-benzodioxepine base compound with a suitable lower S-alkylisothiouronium salt having the requisite number and type of substituentgroups, such as S-methyl isothiouronium sulfate or N,N',S-trimethylisothiouronium hydrochloride, for example; (3) by reacting said aminebase compound with a salt of the appropriate guanylpyrazole, such as asalt of 3,5-dimethyll-guanylpyrazole, to also form the correspondingZ-guanidinoalkyLSA-dihydro2H-1,S-benzodioxepine salt, and (4) byreacting said amine base with a cyanogen halide like cyanogen bromide,followed by treatment of the resulting inter- "ice mediate N-cyanocompound with ammonia or' with an appropriate organic amine to form thecorresponding 2- guanidinoalkyl-3,4-dihydro-2H-1,5 benzodioxepine basecompound.

The starting materials necessary for the above reaction methods leadingto the desired guanidino compounds are either all known compounds orelse they can easily be prepared by those skilled in the art inaccordance with standard organic procedures. For instance, the 2-arninoalkyl-S,4-dihydro-2H-l,5 benzodioxepines required for conversion to theguanidines are easily prepared from known routes starting from thecorresponding carboxylic acid amides which are, in turn, prepared fromthe corresponding carboxylic acids themselves. The amides are thenconverted to the amines by standard reductive methods for thesepurposes. The carboxylic acids concerned are obtainable by routes ofthemselves Well-known in the art, like that described in Belgian PatentNo. 613,212, starting from catec'nol or an appropriately substitutedcatechol.

Tie preferred method employed for preparing the novel compounds of thisinvention involves treating an appropriately substituted2-aminoalkyl-3,4-dihydro 2H- LS-benZodioXepine compound with a suitableS-alkyl isothiouroniurn salt having the requisite substituent groups.This particular reaction is normally carried out in a reaction-inertpolar solvent medium at a temperature ranging from about 20 C. up toabout C. for a period of about one to about 72 hours, and mostconveniently at a temperature ranging from about 60 C. to about 10-0 C.for from about one to twenty hours. In practice, it is generally mostconvenient to heat the two reactants together under reflux in the polarsolvent, employing substantially equimolar amounts of starting materialsfor this purpose although a slight excess of one or the other is notharmful in this respect. The desired S-alkyl isothiouronium saltreagent, of course, is preferably one where the S-alkyl group is loweralkyl in view of relative ease with which such a reaction takes placedue to the more volatile nature of the by-products produced, i.e., thelower boiling mercaptans. Preferred reaction-inert polar solvents foruse in this connection include water, lower al-kanols, such as methanol,ethanol and isopropanol, etc., and N,N-di-( lower alkyl)alkanoamidessuch as N,N- dimethylformamide, N,N dimethylacetamide,N,N-diethylformarnide, N,N diethylacetamide, N,N-'di(n-propyl)formamide,N -N-dirnethylpropionamide, and so forth, as well as lower dialkylsulfoxides and sulfones, such as dimethyl sulfoxide, diethyl sulfone,di-isopropyl sulfoxide and di-n-propylsulfone, etc., and mixtures ofeither of these two aforementioned type organic solvents with water.Upon completion of the reaction, the solvent is removed by means ofconventional procedures and the resulting residue taken upon in asuitable solvent system, such as one of the aforementioned types, fromwhich it can be subsequently crystallized. Alternatively, the productmay separate first from the reaction mixture either during the course ofthe reaction or immediately thereafter, or it may be crystallized fromthe reaction solution after some initial concentration of same. A finalconversion to the desired organic base compound can then be effected bytreating the Z-guanidinoalkyl- 3,4-dihydro-2H-l,S-benzodioxepine acidaddition salt'thus obtained with sufiicient base in water to neutralizesame, e.g., an alkaline reagent such as sodium hydroxide in water can beused. Recovery of the desired free organic base can then be had byextracting the aforesaid aqueous solution with a suitablewater-immiscible organic solvent of low volatility, such as ahalogenated aliphatic hydrocarbon solvent like methylene chloride, forexample.

Of the remaining alternate routes previously discussed in a briefmanner, the most preferred one is the previously mentioned methodinvolving the reaction of a2-aminoalkyl-3,4-dihydro-2H-1,5-benzodioxepine compound, such as2-aminomethyl-3,4-dihydro 2H 1,5-benzodioxepine, with a salt of theappropriate guanylpyrazole base to form the corresponding2-guanidinoalkyl-3,4-dihydro-2H- 1,5-benzodioxepine salt direct. Thepreferred reagent here is a salt of 3,5-dimethyl-l-guanylpyrazole, suchas the corresponding sulfate, but it is also possible to employ otherlower 3,5-dialkyl-l-guanylpyrazole salts in place of3,5-dimethyl-l-guanylpyrazole sulfate and achieve equally satisfactoryresults as well. This particular process is generally carried out byheating the two reactants together in an aqueous solvent medium of thetype previously discussed for the S-alkyl isothiouron-ium method in theabsence of any other reagent. Recovery of the desired product from thereaction mixture is then easily effected by evaporation of same underreduced pressure, followed by the subsequent crystallization of theresultant residue from either water or from an aqueous alcohol mixture.

Inasmuch as most of the products obtained from the foregoingguanidinc-forming reactions of this invention are already in the form oftheir salts, the free guanidine base compounds thereof can thereaftereasily be obtained by simply treating said salts with a suitably strongalkaline base reagent, such as sodium hydroxide, as previouslyindicated. The free base compounds can then be isolated from the aqueousalkaline medium by means of extraction into a suitable water-immiscibleorganic solvent phase, preferably employing one of the lower boilingsolvents such as a halogenated aliphatic hydrocarbon solvent, likemethylene chloride.

Insofar as the 2 guanidinoalkyl-3,4-dihydro-2H-1,5- benzodioxepinecompounds of this invention are basic compounds, they are capable offorming a wide variety of salts with various mineral and organic acids.Although such salts must be pharmaceutically acceptable when the finalproducts are intended for oral consumption, it is possible to firstisolate the desired Z-guanidinoalkyl-3,4-dihydro 2H 1,5-benzodioxepinecompound from the reaction mixture as a pharmaceutically tin--acceptable salt and then to subsequently convert the latter, asindicated previously, to the free base by treatment with an alkalinereagent, followed by the final conversion to the pharmaceuticallyacceptable acid salt in the manner hereinafter indicated. For instance,the acid addition salts of the 2 -guanidinoalkyl-3,4-dihydro-2H-1,5-benzodioxepine compounds of this invention may be prepared bytreating the base compound with a substantially equimolar amounts of thechosen acid. The salt-formation step can be carried out in an aqueoussolution or in a suitable organic solvent such as methanol or ethanol.Upon careful evaporation of the solvent, the

solidsalt is obtained.

H The acids which are used to prepare the pharmaceutically acceptableacid addition salts of the aforementioned 2 guanidinoalkyl-3,4-dihydro2H 1,5-benzodioxepine bases of this invention are those which formnon-toxid acid addition salts containing pharmaceutically acceptableanions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate,sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate,citrate or acid citrate, tartrate or bitartrate, oxalate, succinate,maleate, gluconate, saccharate, methanesulfonate, ethanesulfonate,benzene-sulfonate and p-toluenesulfonate salts.

As previously indicated, the compounds of the present invention are allreadily adapted to therapeutic use as antihypertensive agents, in whichcapacity, incidentally, they are especially active. This is due to theirability to lower the blood pressure of correspondingly agitated subjectsto a statistically significant degree when either orally or parenterallyadministered to them. In addition, they are also useful as potentregulators of the cardiovascular system and are highly elfective asadrenergic neurone blocking agents as well. Furthermore, no problems :of

4 toxicity or any other untoward side effects have ever been encounteredwith any of these compounds in their administration to animals.

In accordance with a method of treatment of the present invention, theherein described antihypertensives can be administered to an agitatedsubject via the oral or parenteral routes. In general, these compoundsare most desirably administered in doses ranging from about 10 mg. up toabout 240 mg. per day, although variations will necessarily occurdepending upon the weight of the subject being treated and theparticular route of administration chosen. However, a dosage level thatis in the range of from about 0.15 mg. to about 4.8 mg. per kg. of bodyweight per day is most desirably employed in order to achieve effectiveresults. Nevertheless, it is to be appreciated that still othervariations may also occur in this respect, depending upon the species ofanimal being treated and its individual response to said medicament, aswell as on the particular type of pharmaceutical formulation chosen andthe time period and interval at which such administration is carriedout. In some instances, dosage levels below the lower limit of theaforesaid range may be more than adequate, while in other cases stilllarger dosages may be employed without causing any harmful ordeleterious side effects to occur provided that such higher dose levelsare first divided into several smaller doses that are to be administeredthroughout the day.

In connection with the use of the 2-guanidinoalkyl-3,4-dihydro-ZH-l,S-benzodioxepine compounds of this invention for thetreatment of agitated subjects, it is to be noted that they may beadministered either along or in combination with pharmaceuticallyacceptable carriers by either of the routes previously indicated, andthat such administration can be carried out in both single and multipledosages. More particularly, the novel compounds of this invention can beadministered in a wide variety of different dosage forms, i.e., they maybe combined with various pharmaceutically acceptable inert carriers inthe form of tablets, capsules, lozenges, troches, hard candies, powders,sprays, aqueous suspensions, injectable solutions, elixirs, syrups, andthe like. Such carriers include solid diluents or fillers, sterileaqueous media and various nontoxic organic solvents, etc. Moreover, suchoral pharmaceutical compositions can be suitably sweetened and/orflavored by means of various agents of the type commonly employed forjust such a purpose. In general, the therapeutically-effective compoundsof this invention are present in such dosage forms at concentrationlevels ranging from about 0.5% to about 90% by weight of the totalcomposition, i.e., in amounts which are suficient to provide the desiredunit dosage previously indicated.

For purposes of oral administration, tablets containing variousexcipients such as sodium citrate, calcium carbonate and dicalciumphosphate may be employed along with various disintegrants such asstarch and preferably potato or tapioca starch, alginic acid and certaincomplex silicates, together with binding agents such aspolyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,lubricating agents such as magnesium stearate, sodium lauryl sulfate andtalc are often very useful for tabletting purposes. Solid compositionsof a similar type may also be employed as fillers in soft andhard-filled gelatin capsules; preferred materials in this connectionwould also include lactose or milk sugar as well as high molecularweight polyethylene glycols. When aqueous suspensions and/or elixirs aredesired for oral administration, the essential active ingredient may becombined with various sweetening or flavoring agents, coloring matter ordyes and, if so desired, emulsifying and/or suspending agents, togetherwith such diluents as water, ethanol, propylene glycol, glycerin andvarious like combinations thereof.

For purposes of parenteral administration, solutions of these particularZ-guanidinoalkyl-3,4-dihydro-2H-1,5- benzodioxepines in sesame or peanutoil or in aqueouspropylene glycol or N,N-dimethylformamide may beemployed, as well as sterile aqueous solutions of the correspondingwater-soluble, non-toxic mineral and organic acid addition saltspreviously enumerated. Such aqueous solutions should be suitablybuffered if necessary and the liquid diluent first rendered isotonicwith sufficient saline or glucose. These particular aqueous solutionsare especially suitable for intravenous, intramuscular, subcutaneous andintraperitoneal injection purposes. In this connection, the sterileaqueous media employed are readily obtained by standard techniqueswell-known to those in the art. For instance, distilled water isordinarily used as the liquid diluent and the final preparation ispassed through a suitable bacterial filter, such as a sintered-glassfilter or a diatomaceous'earth or unglazed porcelain filter, andfinally, into a sterile container with the aid of a suction pump.Needless to say, the necessarysteps should always be taken throughoutthe preparation of these injectable solutions to ensure that the finalproducts are ob tained in a sterile condition.

This invention is further illustrated by the following examples, whichare not to be construed in any way or manner as imposing limitationsupon the scope thereof. On the contrary, it is to be clearly understoodthat resort may be had to various other embodiments, modifications andequivalents thereof which readily suggest themselves to those skilled inthe art without departing from the spirit of the present invention and/or the scope of the appended claims.

Example I A solution of 5.0 g. (0.028 mole) of 2-aminomethyl-3,4-dihydro-2H-1,5-benzodioxepine (Belgian Patent No. 613,212) and 5.22g. (0.014 mole) of 1-guanyl-3,5-dimethylpyrazole sulfate in 100 ml. ofwater was heated on a steam bath for 3 hours. The reaction mixture wasthen cooled to room temperature, and the crude material that separatedwas subsequently collected on a filter funnel by suction filtration.After several recrystallizations of this material from water in thepresence of charcoal,

there were obtained white hygroscopic crystals of pure di(2guanidinomethyl 3,4-dihydro-2H-l,5-benzodioxepine)sulfate melting at255258 C.

AIZHIYSLY-Ciildfor C22H32N 0gSZ C, H, N, 15.55; S, 5.90. Found: C,48.97; H, 6.02; N, 15.35; S, 5.68.

Example II The procedure described in Example I is repeated employing2-aminomethyl-7,8-dichloro-3,4dihydro-2H-1,5- benzodioxepine in place of2-aminomethyl-3,4-dihydro- 2H-l,5-benzodioxepine on the same molar basisas before. In this particular case, the corresponding product obtainedis di(2-guanidinomethyl-7,8-dichloro-3,4-dihydro-2H-1,5- benzodioxepine)sulfate.

In like manner, the use of 2-aminomethyl-6-bromo-3,4-dihydro-ZH-1,5-benzodioxepine as a starting material in this reactionaffords di(2-guanidinomethyl-6-bmine-3,4-dihydro-ZH-1,5-benzodioxepine)sulfate as the final product which isobtained.

Example 111 Example IV The procedure described in Example I is repeatedon the same molar basis as before except thatZ-aminomethyl-7,8-dimethoxy 3,4 dihydro-ZH-1,5-benzodioxepine is thestarting material employed in place ofZ-aminomethyl-3,4-dihydro-2H-l,S-benzodioxepine. In this particularcase, the corresponding product obtained is di(2-guanidinomethyl 7,8dimethoxy-3,4-dihydro-2H-1,S-benzodioxepine)sulfate.

In like manner, the use of Z-arninomethyl-9-isopropoxy-3,4-dihydro-2H-1,5-benzodioxepine as a starting material in thisreaction affordsdi(Z-guanidin0methyl-9-isopropoxy-3,4-dihydro-2H-1,5-benzodioxepine)sulfateas the final product which is obtained.

Example V The procedure described in Example I is followed to preparedi( 2 guanidinomethyl-6-methyl-3,4-dihydro-2l-I-1,S-benzodioxepine)sulfate by reacting 2-aminomethyl-6- methyl 3,4dihydro-ZH-l,S-benzodioxepine and 3,5-dimethyl-l-guanylpyrazole sulfatetogether in ml. of water on an equimolar basis in the same manner ofExample I.

In like manner, the use of Z-aminomethyl-S-(n-propyl)-3,4-dihydro-2I-I-l,S-benzodioxepine as a starting material in thisreaction affords di(2-guanidinomethyl-S-(n-propyl) 3,4-dihydro-ZH-l,S-benzodioxepine)sulfate as the final product which isobtained.

Example VI The procedure described in Example I is repeated with 2(Z-aminoethyl)-3,4-dihydro-2H-1,S-benzodioxepine as the startingmaterial of choice in place of the corresponding methyl compound, usingthe same molar proportions, of course. The particular product obtainedin this case is di[2-(2-guanidinoethyl) 3,4dihydro-2I-I-1,5-benzodioxepine1sulfate.

In like manner, the use of2-(3-aminopropyl)-3,4-dihydro-2H-1,S-benzodioxepine as a startingmaterial in this reaction affords di[2 (3guanidinopropyl)-3,4-dihydro-ZI-I-l,S-benzodioxepine]sulfate as thefinal product which is obtained.

Example VII 2 (N-methyl)aminomethyl-3,4-dihydro-2H-l,5-benzodioxepineand S-methyl isothiouronium sulfate are reacted together in equimolarquantities by refluxing a 30% solution of same in aqueous ethanol for 48hours. Upon completion of this step, the solvent is then removed bymeans of evaporation under reduced pressure to afford a solid residue,which is then subsequently crystallized from ethanol and then fromWater. In this manner, di[2-( 1- methylguanidino)methyl 3,4dihydro-ZH-LS-benzodioxepineJsulfate is the product which is obtained.

In like manner, Z-(N-ethyl)aminomethyl-3,4-dihydro'ZI-I-LS-benzodioxepine affords di[Z- (l-ethylguanidino)methyl-3,4-dihydro-2H-l,S-benzodioxepine]sulfate as the final productwhich is obtained when the former compound is used as the particularstarting material for this reaction.

Example VIII Equimolar amounts of 2-aminomethyl-3,4-dihydro-2I-I-1,5-benzodioxepine and N,N,S-trimethyl isothiouronium hydriodide in a40% by weight solution of same in aqueous dimethylformamide are warmedtogether on a steam bath for six hours. The solvent is then removed fromthe reaction mixture by means of evaporation under reduced pressure toafford a residual oil, which is subsequently made basic with 10 Naqueous sodium hydroxide solution. The resulting aqueous solution isthen extracted with diethyl ether, and the ether extract thus obtainedis dried over anhydrous magnesium sulfate. After removal of the dryingagent by means of filtration and the ether by means of evaporation,there is obtained a residual ma- 7 terial consisting of crude2-(2,3-dimethylguanidinomethyl)-3,4-dihydro-2H-l,S-benzodioxepine.

This material is subsequently dissolved in methanol and added to asolution of excess l-di(p-toluoyl)-D-tartaric acid in the same solvent.Upon the addition of diethyl ether to the mixture, precipitation of thedesired salt soon results and this is recovered by means of suctionfiltration to afford 2-(2,3-dimethylguanidinomethyl)-3,4- dihydro-ZH-l,S-benzodioxepine l-di (p-toluoyl) -D-hydrogen tartrate.

Example IX Ten parts of weight ofdi(2-guanidinomethyl-3,4-dihydro-ZI-I-l,S-benzodioxepine)sulfate in 50parts by volume of water is neutralized with 10 N sodium hydroxidesolution. Extraction of the resulting aqueous solution with severalportions of methylene chloride, followed by separation of the organiclayer and its subsequent concentration under reduced pressure thenaffords Z-guanidinomethyl-3,4-dihydro-2l-l-1,5-benzodioxepine as a freebase.

In like manner, when each of the other 2-guanidinoalkyl-3,4-dihydro-2I-I-1,S-benzodioxepine salts of this invention (forinstance, those salts previously reported in Examples lIVIH) areindividually subjected to this same procedure, the corresponding freeorganic base compound is always the product obtained.

Example X The following Z-guanidinoalkyl 3,4 dihydro-2H-l,5-benzodioxepines are prepared according to the procedures described inthe previous examples from the appropriate starting compounds:

respective organic base compound in absolute ether followed byintroduction of the appropriate hydrogen halide gas into the reactionsolution until saturation of same is complete with respect to said gas,whereupon the desired salt precipitates from solution. The crystallineproduct so obtained is then recrystallized from acetone-ether to yieldthe pure hydrohalide salt. For instance, when 1.0 g. of2-guanidinomethyl-3,4-dihydro-2H-1,5-benzodioxepiue is dissolved inanhydrous diethyl ether and dry hydrogen chloride gas is subsequentlypassed into the resulting solution until saturation of same is completewith respect to said gas, there is obtained a crystalline precipitate of2- guanidinomethyl-3,4-dihydro-2H-1,5 -benzodioxepine hydrochloride.

Example XII The nirtate, sulfate or bisulfate (other than thosepreviously recorded), phosphate or acid phosphate, acetate, lactate,citrate or acid citrate, tartrate or bitartrate,oxalate, succinate,maleate, gluconate, saccharate, methanesulfonate, ethanesulfonate,benzenesulfonate and p-toluenesulfonate salts of each of the2-guanidinoalkyl-3,4- dihydro-ZH-1,5-benzodioxepine bases previouslyreported in Examples IX-X are all prepared by separately dissolving in asuitable amount of ethanol the proper molar amounts of the respectiveacid and the appropriate organic base and then mixing the two solutionstogether, followed by the addition of diethyl ether to the resultingreaction solution in order to effect precipitation of the desired acidaddition salt therefrom. For instance, when equimolar amounts ofN-methyl-Z-(3-methylguanidino) methyl-3,4 dihydro-2I-l-l,5-benzodioxepine and concen- H 8-OC2H5" H Example XI The non-toxichydrohalide acid addition salts of each of the2-guanidinoalkyl-3,4-clihydro-2H-1,5-benzodioxepine bases reportedpreviously in Examples IX-X, such as hydrochloride, hydrobrornide andhydroiodide salts thereof, are individually prepared by first dissolvingthe unou emate-wwmewmwptoipwwwpm pmwpw trated sulfuric acid react inaccordance with this proce- 7 dure, the corresponding product obtainedis di[N-methyl- 2-(3-methylguanidino)methyl3,4-dihydro-2H-1,5-benzodioxepine1sulfate. In like manner, each of theother salts are similarly prepared.

What is claimed is:

1. A compound selected from the class consisting'of 9 Z-guanidinoalkyl3,4-dihydro-2H 1,5 benzodioxepine bases of the formula:

and the mineral and organic acid salts thereof, wherein each of A and Bis a member selected from the group consisting of hydrogen, chlorine,bromine, lower alkyl and lower alkoxy; n is an integer of from one tofour, and each of R R R R and R is a member selected from the groupconsisting of hydrogen and lower alkyl.

2. A compound of claim 1 wherein A, B, R R R R- and R are each hydrogen,and n is an integer of from one to four.

3. A compound of claim 1 wherein A and B are each 10 chlorine, R R R Rand R are each hydrogen and n is an integer of from one to four.

4. A compound of claim 1 wherein A and B are each lower alkoxy, R R R Rand R are each hydrogen and n is an integer of from one to four.

5. A compound of claim 1 wherein A, B, R R R and R are each hydrogen, Ris lower alkyl and n is an integer'of from one to four.

6. Z-guanidinomethyl-3,4-dihydro-2H-1,5 benzodioxepme.

7. 2 guanidinomethyl-7,8-dichl0ro-3,4 dihydro-2H- 1,5-benzodioxepine.

8. 2-(3-guanidinopropyl)-3,4 dihydro 2H-1,5-benzodioxepine.

9. 2-(1-methylguanidino)methy1 3,4-dihydro 2H- 1,5-benzodioxepine.

10. 2-guanidinomethyl-3-methyl-3,4-dihydro 2H-1,5- benzodioxepine.

No references cited.

ALEX MAZEL, Primary Examiner.

J. H. TURNIPSEED, Assistant Examiner.

1. A COMPOUND SELECTED FROM THE CLASS CONSISTING OF 2-GUANIDINOALKYL-3,4-DIHYDRO-2H - 1,5-BENZODIOXEPINE BASES OF THE FORMULA: